Tripartite motif containing 27 alleviated septic liver injury via the HSPA8/JNK pathway in mice.

Abstract

Liver dysfunction predicts poor outcome in patients with sepsis, with a lack of effective treatment, emphasizing the critical need for innovative therapeutic strategies. Tripartite motif containing 27 (TRIM27) plays vital roles in pyroptosis, inflammation, and autophagy. However, the impact of TRIM27 on septic liver injury remains unclear. In this study, the mice were injected with adeno-associated virus 8 for generating the hepatocyte-specific overexpression of TRIM27 mice and control littermates, and subsequently underwent a cecal ligation and puncture operation. Hepatocytes were challenged with lipopolysaccharide to simulate the sepsis-related damage. Liver damage was associated with the downregulation of Trim27 induced by sepsis in hepatocytes. Trim27 overexpression ameliorated liver injury and hepatocyte damage in vivo and in vitro. Mechanically, TRIM27 bound to HSPA8 via its SPRY domain and modified HSPA8 by ubiquitination. This interaction inhibited JNK phosphorylation and mitigated inflammatory responses. Silencing Hspa8 partially offset TRIM27's cytoprotective function whereas overexpressing HSPA8 enhanced this protective effect. These findings clarified that TRIM27 mitigated sepsis-related inflammatory responses by binding to HSPA8 to inhibit JNK activation in hepatocytes, suggesting TRIM27 as a prospective target for treating septic liver injury.